Human African trypanosomiasis (HAT) is an infectious disease with a large global health burden occurring primarily in Central and Eastern Africa. HAT is 100% fatal if untreated and the current drug therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and high costs. Furthermore, drugs that cross the blood brain barrier (BBB) are notoriously difficult to develop and have a lower probability of reaching the market place. Here, we propose to apply a quantum-similarity approach to discover novel T. Brucei inhibitors. The approach allows for simultaneous interrogation of multiple targets and pathways, and for incorporation of various pharmacological requirements early in the discovery process, thus increasing the chances of finding novel therapeutics with great selectivity, potency and pharmacokinetic properties. Instead of screening millions of compounds for novel modulators of the target of interest, our focused testing of 10-20 commercially available compounds per target (pathway, protein etc.) with predicted (inhibitory) activity by the modeling effort, allows us to quickly explore novel chemical spaces for therapeutic applications. The modeling, virtual search, identification and rank ordering of novel classes T. brucei inhibitors, as well as the de novo design of novel anti-trypanosome drug candidates will be done by Gradient Biomodeling. The experimental evaluation of the compounds will be done in the laboratory of Dr. Kojo Mensa-Wilmot at the University of Georgia.